Tetrahydrobenzazepine derivatives which inhibit lipoxygenase

ABSTRACT

Compounds of the formula ##STR1## wherein n is 1 to 5 and R is hydrogen, C 1  to C 4  alkyl, arylalkyl having from one to four carbon atoms in the alkyl moiety or arylalkyl substituted with one or more substituents selected independently from the group consisting of halogen, nitro, cyano, C 1  to C 6  alkyl, C 1  to C 6  alkoxy, C 1  to C 6  halosubstituted alkyl, C 1  to C 6  hydroxysubstituted alkyl, C 2  to C 7  alkoxycarbonyl and aminocarbonyl, and the pharmaceutically acceptable salts thereof, inhibit the enzyme lipoxygenase and are useful in treating allergy and inflammatory and cardiovascular conditions for which the action of lipoxygenase has been implicated. These compounds form the active ingredient in pharmaceutical compositions for treating such conditions.

This application is a 371 of PCT/US 92/04197 filed May 27, 1992.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel tetrahydrobenzazepine N-hydroxyureaderivatives. The compounds of the present invention inhibit the actionof the enzyme lipoxygenase and are useful in the treatment oralleviation of inflammatory diseases, allergy and cardiovasculardiseases in mammals. This invention also relates to pharmaceuticalcompositions comprising such compounds and to the use of such compoundsin treating inflammatory diseases, allergy and cardiovascular diseasesin mammals. This invention further relates to methods of making suchcompounds.

Arachidonic acid is known to be the biological precursor of severalgroups of endogenous metabolites, prostaglandins includingprostacyclins, thromboxanes and leukotrienes. The first step ofarachidonic acid metabolism is the release of arachidonic acid andrelated unsaturated fatty acids from membrane phospholipids, via theaction of phospholipase. Free fatty acids are then metabolized either bycyclooxygenase to produce the prostaglandins and thromboxanes or bylipoxygenase to generate hydroperoxy fatty acids which may be furtherconverted to the leukotrienes. Leukotrienes have been implicated in thepathophysiology of inflammatory diseases, including rheumatoidarthritis, gout, asthma, ischemia reperfusion injury, psoriasis andinflammatory bowel disease. Any drug that inhibits lipoxygenase isexpected to provide significant new therapy for both acute and chronicinflammatory conditions.

Several review articles on lipoxygenase inhibitors have been reported(See H. Masamune et al., Ann. Rep, Med. Chem., 24, 71-80 (1989) and B.J. Fitzsimmons et al., Leukotrienes and Lipoxygenases, 427-502 (1989).

Compounds of the same general class as the compounds of the presentinvention are disclosed in EP 279263 A2, EP 196184 A2, JP (Kohyo)502179/88 and U.S. Pat. No. 4,822,809.

SUMMARY OF THE INVENTION

The present invention provides novel tetrahydrobenzazepine N-hydroxyureaderivatives of the following formula and their pharmaceuticallyacceptable salts: ##STR2## wherein n is 1 to 5; R is hydrogen, C₁ to C₄alkyl, arylalkyl having from one to four carbon atoms in the alkylmoiety or arylalkyl substituted with one or more substituents selectedindependently from the group consisting of halogen, nitro, cyano, C₁ toC₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆ halosubstituted alkyl, C₁ to C₆hydroxysubstituted alkyl, C₂ to C₇ alkoxycarbonyl and aminocarbonyl.

This invention also concerns pharmaceutical compositions comprising apharmaceutically acceptable carder or diluent and a compound of theinvention or a pharmaceutically acceptable salt thereof. This inventionfurther concerns methods of treating inflammatory diseases, allergy andcardiovascular diseases in mammals comprising administration of suchcompounds or compositions.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following definitions are used.

"Halo" and "halogen" mean radicals derived from the elements fluorine,chlorine, bromine and iodine.

"Alkyl" means straight or branched saturated hydrocarbon radicals, forexample, methyl, ethyl, n-propyl and isopropyl.

"Alkoxy" means --OR¹ wherein R¹ is an alkyl radical, for example,methoxy, ethoxy, propoxy, isopropoxy and butoxy.

"Alkoxycarbonyl" means --C(═0)R² wherein R² is an alkoxy radical, forexample, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

"Arylalkyl" means an aromatic radical appended to an alkyl radical, forexample, phenylethyl(benzyl), phenylethyl, phenylpropyl, phenylbutyl andnaphthylmethyl.

"Hydroxysubstituted alkyl" refers to an alkyl radical as described abovesubstituted with one or more hydroxy radicals, for example,hydroxymethyl, dihydroxyethyl and trihydroxypropyl.

Some of the compounds of the above formula may form acid salts. Thepharmaceutically acceptable acid salts are those formed from acids whichform non-toxic acid salts, for example, hydrochloride, hydrobromide,sulfate or bisulfate, phosphate or acid phosphate, acetate, citrate,fumarate, gluconate, lactate, maleate, succinate, tartrate,methansulfonate, benzensulfonate, toluene-sulfonate, and formate salts.

This invention includes pharmaceutical compositions for treatment ofinflammatory diseases, allergy and cardiovascular diseases in a mammalwhich comprises a pharmaceutically acceptable carder or diluent and acompound of the above formula or a pharmaceutically acceptable saltthereof.

This invention also includes pharmaceutical compositions for inhibitingthe lipoxgenase in a mammal which comprises a pharmaceuticallyacceptable carrier and a compound of the above formula or apharmaceutically acceptable salt thereof.

The novel compounds of this invention may be prepared as shown in thereaction scheme described below. ##STR3##

The compounds of the invention may be prepared by a number of syntheticmethods. Except where otherwise indicated, in the above reaction schemeand discussion that follow, R and n are as previously defined.

In one embodiment, the compounds of the invention (v) are preparedaccording to the reaction steps explained in detail as follows.

The starting materials used in the procedure of the above reactionscheme may be prepared from commercially available compounds or knowncompounds according to standard methods known in the art.

In the first step, aldehyde derivatives (ii) are easily prepared fromthe corresponding benzazepine derivatives (i) by standard methods knownin the art (Vilsmeier reaction).

Generally, the reaction is run for several minutes to several hours. Thereaction temperature may range from room temperature to about 100° C.Suitable N-disubstituted formamide agents are selected fromN,N-dimethylformamide (DMF) and N-methyl-N-formanilide (MFA). Suitablechloride agents are selected from phosphorus oxychloride (POCl₂) andthionyl chloride (SOCl₂). If necessary, dichloromethane can be utilizedas a reaction-inert solvent. The product can be isolated and purified byconventional procedures, such as recrystallization or chromatography.

In the second step, the aldehyde (ii) is treated with hydroxylaminehydrochloride to afford the oxime (iii). This reaction is carded out ina reaction-inert solvent in the presence of suitable base such aspyridine or triethylamine usually at room temperature. Suitable solventswhich do not react with reactants and/or products include, for example,ethanol, THF and mixtures thereof. The oxime (iii) thus obtained isisolated by standard methods. Without further purification, in the nextstep, the oxime (iii) is converted to the requisite hydroxylamine (iv)with a suitable reducing agent (for example, see R. F. Borch et al, J.Am. Chem. Soc., 93, 2897 (1971)). Reducing agents of choice include, butare not limited to, sodium cyanoborohydride and borane-complexes such asboron-pyridine, boron-triethylamine and boron-dimethylsulfide, however,triethylsilane in trifluoroacetic acid may also be employed.

The aforementioned hydroxylamine (iv) is easily prepared by standardsynthetic procedures from readily available carbonyl compounds, i.e,ketone, aldehyde, alcohol or halogen compounds (for example, see R. L.Danheiser et al., Tetrahedron Lett., 28, 3299 (1987), M. Kolobieiski etal., J. Am. Chem. Soc., 79, 5820 (1957), Y. Kobayashi et al., J. Org.Chem., 47, 3232 (1982) and Fieser et al., J. Am. Chem. Soc., 70, 3147(1948)).

Alternatively the hydroxylamine (iv) can be prepared by treating thecorresponding alcohol with N,O-bis(tert-butyloxycarbonyl)hydroxylamineunder Mitsunobu-type reaction conditions followed by acid catalyzedhydrolysis of the N,O-protected intermediate product (see JP(Kokai)45344/89).

The aforementioned hydroxylamine (iv) may also be prepared from asuitable halide compound by reaction with O-protected hydroxylamine andsubsequent deprotection (see W. P. Jackson et al., J. Med. Chem., 31,499 (1988)). Preferred O-protected hydroxylamines include, but are notlimited to, O-tetrahydropyranyl-, O-trimethylsilyl- andO-benzylhydroxylamine.

The hydroxylamine of formula (iv) thus obtained by the abovementionedrepresentative procedures is isolated by standard methods andpurification can be achieved by conventional means, such asrecrystallization and chromatography.

In the last step, the hydroxylamine (iv) is treated withtrimethylsilylisocyanate (TMS-NCO) in a reaction-inert solvent usuallyat ambient through to reflux temperature. Suitable solvents which do notreact with reactants and/or products include, for example,tetrahydrofran, dioxane, methylene chloride and benzene. An alternativeprocedure employs treatment of the hydroxylamine (iv) with gaseoushydrogen chloride in a reaction-inert solvent such as benzene or tolueneand then subsequent treatment with phosgene, Reaction temperatures areusually in the range of ambient temperature through to boiling point ofsolvent. The intermediate carbamoyl chloride is not isolated butsubjected to (i.e. in situ) reaction with aqueous ammonia. The ureacompound (v) thus obtained is isolated by conventional means, such asrecrystallization and chromatography.

The pharmaceutically acceptable salts of the novel compounds of thepresent invention are readily prepared by contacting said compounds witha stoichiometric amount of, in the case of a non-toxic cation, anappropriate metal hydroxide or alkoxide or amine in either aqueoussolution or a suitable organic solvent, or, in the case of a non-toxicacid salt, an appropriate mineral or organic acid in either aqueoussolution or a suitable organic solvent. The salt may then be obtained byprecipitation or by evaporation of the solvent.

The compounds of this invention inhibit the activity of the enzymelipoxygenase. This inhibition has been demonstrated by an assay usingrat peritoneal cavity-resident cells which determines the effect of saidcompounds on the metabolism of arachidonic acid.

All of the compounds of Examples 1 to 4 were tested according to themethods described in "Synthesis of leukotrienes by peritonealmacrophages," Jap. J. Inflammation, 7, 145-150 (1987), and were shown tobe lipoxygenase inhibitors, exhibiting IC₅₀ values in the range of about0.199 to about 3.16 μM, for lipoxygenase inhibition.

The ability of the compounds of the present invention to inhibitlipoxygenase makes them useful for controlling the symptoms induced bythe endogenous metabolites arising from arachidonic acid in a mammaliansubject. The compounds are therefore valuable in the prevention andtreatment of such disease states in which the accumulation ofarachidonic acid metabolites are the causative factor, e.g., allergicbronchial asthma, skin disorders, rheumatoid arthritis, osteoarthritisand thrombosis.

The compounds of formula (I) and their pharmaceutically acceptable saltsare of particular use in the treatment or alleviation of inflammatorydiseases, allergy and cardiovascular diseases in a human subject as wellin the inhibition of lipoxygenase.

Methods of Administration

For treatment of the various conditions described above, the compoundsof the invention and their pharmaceutically acceptable salts can beadministered to a human subject either alone or, preferably, incombination with pharmaceutically acceptable carders or diluents in apharmaceutical composition, according to standard pharmaceuticalpractice. A compound can be administered via a variety of conventionalroutes of administration including orally, parenterally and byinhalation. When the compounds are administered orally, the dose rangewill generally be from about 0.1 to about 20 mg/kg/day, based on thebody weight of the subject to be treated, preferably from about 0.1 toabout 1.0 mg/kg/day in single or divided doses. If parenteraladministration is desired, then an effective dose will generally be fromabout 0.1 to about 1.0 mg/kg/day. In some instances it may be necessaryto use dosages outside these limits, since the dosage will necessarilyvary according to the age, weight and response of the individual patientas well as the severity of the patient's symptoms and the potency of theparticular compound being administered.

For oral administration, the compounds of the invention and theirpharmaceutically acceptable salts can be administered, for example, inthe form of tablets, powders, lozenges, syrups or capsules, or as anaqueous solution or suspension. In the case of tablets for oral use,carriers which are commonly used include lactose and corn starch.Lubricating agents such as magnesium stearate are commonly added. In thecase of capsules, useful diluents are lactose and dried corn starch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents can be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, asterile solution of the active ingredient is usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solute should be controlledto make the preparation isotonic.

EXAMPLES

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHzunless otherwise indicated and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane. The peak shapes aredenoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad.

Example 1N-Hydroxy-N-(1-benzyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)methylurea##STR4## Step 1, 1-Benzyl-1H-1-benzazepin-7-carboxaldehyde

Phosphorus oxychloride (1.9 ml, 20.4 retool) was added to DMF (10 ml) atambient temperature and the mixture was stirred for 30 minutes undernitrogen atmosphere. To the mixture was added crude1-benzyl-1H-1-benzazepine (3.23 g, 13.6 mmol) in DMF (5 ml) at ambienttemperature. The mixture was stirred at ambient temperature for 1 hourand at 70° C. for 2 hours. Water (35 ml) was added and the mixture wasstirred for 10 minutes. The mixture was extracted with EtOAc (2×100 ml)and the combined extracts were washed with H₂ O (2×50 ml), saturatedNaHCO₃ solution (50 ml) and brine (50 ml). The solution was dried overMgSO₄ and concentrated in vacuo affording the title compound as a brownoil (3.42 g).

¹ H NMR (270 MHz, CDCl₃) δ 9.77 (s, 1H), 7.63-7.50 (m, 2H), 7.40-7.20(m, H), 6.85 (d, J=7.9 Hz, 1H), 4.48 (s, 2H), 3.30-3.20 (m, 2H),3.00-2.90 (m, 2H), 1.89-1.63 (m, 4H).

Step 2,N-Hydroxy-N-(1-benzyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)-methylurea

To a solution of 1-benzyl-1H-1-benzazepin-7-carboxaldehyde (3.42 g, 12.9mmol) in pyridine (6.5 ml) and EtOH (6.5 ml) was added H₂ N-OH.HCl (1.34g, 19.3 mmol) and the mixture was stirred at ambient temperature for 1hour, concentrated in vacuo and extracted with EtOAc (100 ml) and H₂ O(80 ml). The aqueous layer was extracted with EtOAc (30 ml). Thecombined extracts were washed with H₂ O (2×50 ml) and brine (30 ml). Thesolution was dried over MgSO₄ and concentrated in vacuo to give a brownoil (3.60 g). Without purification, the oxime (3.60 g, 12.8 mmol) wasdissolved in AcOH (12 ml) and NaBH₃ CN (1.02 g, 16.2 mmol) was addedportionwise over a period of 45 minutes and the mixture was stirred for1 hour. To the mixture was added dropwise 10N NaOH (10 ml) under icebath and the mixture was brought to pH 9 with the addition of Na₂ CO₃.The mixture was extracted with EtOAc (2×30 ml) and the combined extractswere washed with H₂ O (2×50 ml) and brine (50 ml). The solution wasdried over MgSO₄ and concentrated in vacuo to afford the correspondinghydroxylamine as yellow oil (3.31 g, 92% yield). Without purification,the product was dissolved in THF (12 ml) and to the solution was added90% TMSN═C═O (2.4 ml, 17.6 mmol) and the mixture was stirred at ambienttemperature overnight. Water (2 ml) was added to the mixture, which wasthen stirred for 10 minutes. The mixture was concentrated in vacuoaffording a yellow oil (4.2 g). Chromatography on silica gel (100 g)eluted with CH₂ Cl₂ :EtOH:EtOAc (30:1:1) afforded a colorless oil (3.01g). Crystallization from EtOAc afforded the title compound as a whitesolid (1.06 g, 24% overall yield), m.p. 81.6°-83.4° C. (dec.).

IR v (KBr): 3450, 3200, 2920, 1650.

NMR δ (DMSO): 9.25 (s, 1H), 7.41 (d, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz,2H), 7.23 (t, J=7.5 Hz, 1H), 7.04-6.96 (m, 2H), 6.91 (d, J=8.1 Hz, 1H),6.25 (s, 2H), 4.39 (s, 2H), 4.29 (s, 2H), 2.88-2.73 (m, 4H), 1.64-1.46(m, 4H).

Example 2N-Hydroxy-N-[1-(3-methoxybenzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]methylurea##STR5##

The title compound, m.p. 38°-42° C., was synthesized according to theprocedure of Example 1 from 1-(3-methoxybenzyl)-1H-1-benzazepine.

IR v (KBr): 3500, 3400, 1740, 1650.

NMR δ (DMSO): 9.24 (s, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.04-6.94 (m, 4H),6.89 (d, J=8.1 Hz, 1H), 6.79 (dd, J=8.1,-2.2 Hz, 1H), 6.27 (s, 2H), 4.39(s, 2H), 4.26 (s, 2H), 3.73 (s, 3H), 2.86-2.74 (m, 4H), 1.65-1.46 (m,4H).

Example3N-Hydroxy-N-(1-ethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)methylurea##STR6##

The title compound was synthesized according to the procedure of Example1 from 1-ethyl-1H-1-benzazepine.

IR v (CHCl₃): 2930, 1680, 1565, 1505.

NMR δ (DMSO): 9.23 (s, 1H), 7.03-6.96 (m, 2H), 6.82 (d, J=7.7 Hz, 1H),6.26 (s, 2H), 4.39 (s, 2H), 3.10 (q, J=7.7 Hz, 2H), 2.87-2.79 (m, 2H),2.71-2.62 (m, 2H), 1.70-1.58 (m, 2H), 1.58-1.45 (m, 2H), 1.11 (t, J=7.7Hz, 3H).

Example 4N-Hydroxy-N-[3-(1-ethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)propyl]urea##STR7##

The title compound was synthesized according to the procedure of Example1 from 1,7-diethyl-1H-1-benzazepine.

IR v (CHCl₃): 2930, 1655, 1570, 1505.

NMR δ (DMSO): 9.22 (s, 1H), 6.96-6.87 (m, 2H), 6.79 (d, J=8.4 Hz, 1H),6.24 (s, 2H), 3.46-3.25* (2H), 3.07 (q, J=7.0 Hz, 2H), 2.85-2.77 (m,2H), 2.69-2.61 (m, 2H), 2.45 (t, J=7.7 Hz, 2H), 1.73 (t, J=7.1 Hz, 2H),1.69-1.58 (m, 2H), 1.56-1.44 (m, 2H), 1.10 (t, J=7.0 Hz, 3H).

We claim:
 1. A compound of the formula ##STR8## or a pharmaceuticallyacceptable salt thereof, wherein: n is 1;R is hydrogen, C₁ to C₄ alkyl,or arylalkyl, wherein in said arylalkyl the aryl moiety is a phenyl ornaphthyl group and the alkyl moiety has from one to four carbon atoms,and wherein said arylalkyl is optionally substituted by one or moresubstituents selected independently from the group consisting ofhalogen, nitro, cyano, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆halosubstituted alkyl, C₁ to C₆ hydroxysubstituted alkyl, C₂ to C₇alkoxycarbonyl and aminocarbonyl.
 2. A compound according to claim 1wherein R is C₁ to C₄ alkyl.
 3. A compound according to claim 1 whereinR is arylalkyl or substituted arylalkyl.
 4. A compound according toclaim 2 wherein R is ethyl.
 5. A compound according to claim 3 wherein Ris arylalkyl.
 6. A compound according to claim 3 wherein R issubstituted arylalkyl.
 7. A compound according to claim 5 wherein R isbenzyl.
 8. A compound according to claim 6 wherein R is methoxybenzyl.9. The compound of claim 1 wherein the compound is selected from thegroup consisting ofN-Hydroxy-N-(1-benzyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)methylurea,N-hydroxy-N-[1-(3-methoxybenzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl]methylurea,andN-Hydroxy-N-(1-ethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-7-yl)methylurea.10. The compound of claim 1 wherein R is arylalkyl and wherein in saidarylalkyl the aryl moiety is a phenyl group that optionally includes oneor more substituents.
 11. The compound of claim 1 wherein R is a methylgroup.
 12. A pharmaceutical composition for the treatment of allergy,inflammatory or cardiovascular conditions in a mammal comprising atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier.
 13. A method of inhibitinglipoxygenase in a mammal comprising administering to said mammal alipoxygenase-inhibiting amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 14. A method of treatingallergy or inflammatory or cardiovascular conditions in a mammalcomprising administering to said mammal a lipoxygenase-inhibiting amountof a compound according to claim I or a pharmaceutically acceptable saltthereof.